The cognitive profile of type 1 Gaucher disease patients.

BACKGROUND: The absence of neurological symptoms and signs is traditionally considered mandatory for a diagnosis of type 1 Gaucher disease (GD1), but in recent years many reports have emerged on neurological manifestations in GD1 patients. Nevertheless, it has been unclear whether cognitive deficits are part of the disease as well. METHODS: Cognitive function was assessed in a large cohort of GD1 patients with the use of the CDR system, a set of computerised cognitive tests. Testing was performed at baseline and every 6 months thereafter during a two-year study period. RESULTS: Our patient cohort (84 patients, median age 40 years, median time from diagnosis 15 years) showed mild deficits relative to healthy age-matched subjects on the composite scores: power of attention (Z-score (mean ± SD) -0.9 ± 1.37) and speed of memory (Z-score (mean ± SD) -1.39 ± 1.49). No decline in cognitive function was seen during the two-year period. Age correlated with the composite scores variability of attention and quality of working memory. Moreover, severely affected patients (Zimran severity score (SSI) ≥ 15) scored more poorly compared to mildly affected patients (SSI ≤ 5) on the composite measure power of attention, reflecting the ability to concentrate. CONCLUSIONS: GD1 patients exhibit mild deficits in power of attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory. The clinical relevance of these findings is uncertain.

Efficacy and safety of colistin in the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa in patients with hematologic malignancy: a matched pair analysis.

OBJECTIVE: A rise in infections with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is a significant contributor to increased morbidity and mortality of patients with hematologic malignancies. The aim of this study was to determine the efficacy and safety of colistin (colistimethate sodium) in the treatment of serious infections caused by MDR-PA in these patients. PATIENTS AND METHODS: A matched pair analysis of renal function, toxicities, and outcome of 26 patients receiving colistin and control subjects was done. All patients had clinical signs of sepsis; P. aeruginosa was isolated from blood in 69% of patients in colistin group and 84% in control group. Patients treated with colistin received 3 million units every 8 hours for a median duration of 13 days. Additionally, patients received at least two additional antimicrobial or antifungal drugs. RESULTS: Resolution of infection was achieved in twenty patients (76.9%) receiving colistin and in 17 (65.4%) control subjects. Mortality rate was 11% in both groups. There was no statistically significant difference in the level of serum creatinine, creatinine clearance, or potassium levels before and after treatment between groups. Only one patient receiving colistin developed de novo renal failure and one displayed transient neurologic toxicity. CONCLUSION: Our results suggest that in patients with hematologic malignancies, colistin is effective in treating severe infections caused by MDR-PA while maintaining an acceptable toxicity profile. Prospective randomized studies comparing efficacy and safety of colistin with those of other antipseudomonal drugs are needed.

Peripheral neuropathy in adult type 1 Gaucher disease: a 2-year prospective observational study.

Type 1 Gaucher disease is currently categorized as non-neuronopathic, although recent studies suggest peripheral neurological manifestations. We report prevalence and incidence data for peripheral neuropathy and associated conditions from a multinational, prospective, longitudinal, observational cohort study in patients with type 1 Gaucher disease, either untreated or receiving enzyme replacement therapy. The primary outcome parameters were the prevalence and incidence of polyneuropathy, evaluated by standardized assessments of neurological symptoms and signs, and electrophysiological studies. All diagnoses of polyneuropathy were adjudicated centrally. Secondary outcome parameters included the prevalence and incidence of mononeuropathy, other neurological or electrophysiological abnormalities not fulfilling the criteria for a mono- or polyneuropathy and general type 1 Gaucher disease symptoms. Furthermore, a literature search was performed to identify all studies reporting on prevalence and incidence of polyneuropathy in the general population. One hundred and three patients were enrolled [median (range) age: 42 (18-75) years; disease duration: 15 (0-56) years; 52% female]; 14 (13.6%) were untreated and 89 (86.4%) were on enzyme replacement therapy. At baseline, 11 patients [10.7%; 95% confidence interval (CI): 5.9-18.3] were diagnosed with sensory motor axonal polyneuropathy. Two (1.9%; 95% CI: 0.1-7.2) had a mononeuropathy of the ulnar nerve. The 2-year follow-up period revealed another six cases of polyneuropathy (2.9 per 100 person-years; 95% CI: 1.2-6.3). Patients with polyneuropathy were older than those without (P<0.001). Conditions possibly associated with polyneuropathy were identified in four patients only, being monoclonal gammopathy, vitamin B(1) deficiency, folic acid deficiency, type 2 diabetes mellitus, renal insufficiency, alcohol abuse and exposure to toxins related to profession. The 11 cases of polyneuropathy found at baseline were confirmed during follow-up. According to the literature, the prevalence of polyneuropathy in the general population was estimated between 0.09 and 1.3% and the incidence was estimated between 0.0046 and 0.015 per 100 person-years. Thus, we conclude that the prevalence and incidence of polyneuropathy in patients with type 1 Gaucher disease is increased compared with the general population.

Collection and composition of autologous peripheral blood stem cells graft in patients with acute myeloid leukemia: influence on hematopoietic recovery and outcome.

Hematopoietic stem cell (HSC) transplantation is a standard approach in the treatment of hematological malignant diseases. For the last 15 years the main source of cells for transplantation have been peripheral blood stem cells (PBSC). With the availability of hematopoietic growth factors and understanding the advantages of treatment with PBSC, the application of bone marrow (BM) was supplanted. The aim of this survey was to explore the success of PBSC collection, the factors which influence the success of PBSC collection, the composition and the quality of graft and their influence on hematopoietic recovery and outcome after transplantation in patients with acute myeloid leukemia (AML). PBSC were collected by the method of leukapheresis after applying a combination of chemotherapy and growth factors or only growth factors. The quality of graft was determined with the clonogenic progenitor cell assay and with the flow cytometry analysis. Of the total 134 patients with AML, who were submitted to HSC mobilization, the collection was successful in 78 (58.2%) patients. The collection was more successful after the first than after the second attempt of HSC mobilization (49% vs. 11%). The criteria for effective mobilization were the number of leukocytes > 3 x 10(9)/L and the concentration of CD34+ cells > 20 x 10(3)/mL in the peripheral blood on the first day of leukapheresis. The number of CD34+ cells infused had the strongest impact on hematopoietic recovery. We noted significantly faster hematological recovery of neutrophils and platelets, fewer number of transfused units of red blood cells and platelets, shorter duration of the tranfusion support, shorter treatment with intravenous antibiotic therapy and shorter hospitalization after PBSC compared to BM transplantation. These advantages could provide their standard application in the treatment of patients with AML.

[Treatment of acute leukemia with allogeneic stem cell transplantation]. / Lijecenje akutnih leukemija transplantacijom alogenicnih maticnih stanica.

Allogeneic hematopoietic stem cell transplantation is a standard therapeutic option in the treatment of patients with malignant hematologic diseases and some acquired or inherited nonmalignant hematologic disorders. It is the most efficacious method for eradication of acute leukemia, its efficacy being described by DFS (Disease Free Survival) and OS (Overall Survival), however, still associated with a high Transplant Related Mortality (TRM) rate. At Department of Hematology, University Department of Medicine, Zagreb University Hospital Center, bone marrow transplantation has been a standard procedure since 1983. Since that time, 281 patients with acute leukemia have undergone allotransplantation at our Department. Results are presented of 72 patients with acute myeloid leukemia transplanted at our Department during the 1993-2007 period.

[Twenty years of severe aplastic anemia treatment at Department of Hematology, University Department of Medicine, Zagreb University Hospital Center, Zagreb, Croatia]. / Dvadeset godina lijecenja teske aplasticne anemije u Zavodu za hematologiju Klinike za unutrasnje bolesti Klinickog bolnickog centra Zagreb.

Aplastic anemia is a bone marrow disease characterized by marrow aplasia and pancytopenia. Because hematopoietic stem cell transplantation (HSCT) cures severe aplastic anemia (SAA), it is the treatment of choice for younger patients. For many years, antithymocyte globulin (ATG) has been standard immunosuppressive therapy for those aplastic anemia patients that have no HLA matched related donor. ATG significantly improves aplastic anemia outcome, especially when combined with cyclosporine (CSP). The response rate varies from 40% to 70% and long-term survival is comparable with patients receiving marrow transplant. From 1983 until 2006, 46 SAA patients received HLA identical sibling marrow graft. In the same period, 50 patients received standard immunosuppressive therapy combined from horse or rabbit ATG, 6 methyl prednisolone and cyclosporine. Out of 46 transplant patients, 27 received a combination of cyclophosphamide and thoraco-abdominal irradiation. The overall probability of survival for SAA patients that underwent marrow grafting is 51%, and for patients receiving immunosuppressive treatment 20%. We analyzed a cohort of patients receiving treatment after 1990 and found the probability of survival to be 64% for bone marrow transplanted patients and 36% for patients receiving immunosuppression. Infection is the main cause of death in both groups. In conclusion, we documented improving results using ATG in patients with SAA.

The female Gaucher patient: the impact of enzyme replacement therapy around key reproductive events (menstruation, pregnancy and menopause).

BACKGROUND: The principal manifestations of type 1 Gaucher disease (GD) (increased risk of bleeding, anaemia, splenomegaly, hepatomegaly and bone disease) are likely to affect females during reproductive events such as menarche and menstruation; fertility, pregnancy, parity, delivery and lactation; and menopause. In order to determine the optimal management of female Gaucher patients based on available data, we examine reproductive events and GD in untreated and alglucerase and/or imiglucerase-treated females. METHODS: A panel of international clinicians experienced in the management of GD reviewed and presented evidence from peer-reviewed literature, a pharmacovigilance database on imiglucerase, and their own clinical experience to support discussions and recommendations. Nine panel members completed a 130-item-questionnaire on the outcomes of the management of female patients in their clinical practice. Results, covering menarche (137 females), menstruation (261 reports), fertility (295 females), pregnancy (416 pregnancies in 247 women) and menopause (45 women) were analysed. Data from a recent Canadian survey on 50 patients with 39 pregnancies, the imiglucerase pharmacovigilance database (100 pregnancies), and relevant literature (56 items covering 398 pregnancies in 205 women) were also reviewed. KEY RESULTS: Menarche: May be delayed in girls with GD. Menorrhagia: Appears to be more common in GD than in the non-Gaucher population and may be ameliorated by alglucerase and/or imiglucerase treatment (menorrhagia in 67/133 (50.4%) untreated females compared with 37/128 (28.9%) treated; Mann-Whitney U test: p=0.001). Fertility: There is no evidence of decreased fertility in GD. Pregnancy: Pregnancy in GD may be complicated by haematological disease, organomegaly and bone involvement. GD diagnosis occurs frequently during pregnancy. Questionnaire results demonstrate: a reduced risk of spontaneous abortion in women treated with alglucerase and/or imiglucerase (untreated: 26/189 (13.8%); treated 1/58 (1.7%) chi(2)p=0.010); reduced risk of Gaucher-related complications during delivery (untreated 43/109 (39.4%); treated 3/46 (6.5%) chi(2)p<0.0005): and a reduced risk of Gaucher-related complications during the post partum period (untreated 15/71 (21.1%); treated 3/43 (7%) chi(2)p=0.014). There is no evidence to date of any untoward effect of alglucerase and/or imiglucerase on the fetus, or on infants breast fed by mothers receiving alglucerase and/or imiglucerase. Menopause: The impact of GD on menopause requires further study especially in relation to bone pathology. CONCLUSIONS: On the basis of this review, GD may have an impact on reproductive events in affected women. Enzyme therapy may have benefits in reducing menorrhagia, spontaneous abortions and complications associated with delivery and the postpartum period.

Pre-medication practices and incidence of infusion-related reactions in patients receiving AMPHOTEC: data from the Patient Registry of Amphotericin B Cholesteryl Sulfate Complex for Injection Clinical Tolerability (PRoACT) registry.

BACKGROUND: Clinical studies have suggested that rates of infusion-related reactions (IRRs) may be higher with amphotericin B colloidal dispersion (ABCD) versus other forms of amphotericin B. However, these studies did not permit the use of pre-medications upfront, which are now commonly used. Objectives To describe the use of pre-medications and determine the rate of IRRs in the real-world setting. METHODS: PRoACT, a multicentre, worldwide observational registry, captured real-world data about pre-medication practices and IRRs in patients receiving ABCD. Eligible patients were those beginning treatment with ABCD; treatment was according to the site's standard treatment practice. Incidence of IRRs was collected during the first 10 days of ABCD therapy. Clinical response data were collected 12 weeks after treatment start. RESULTS: One hundred and seventy patients from 21 worldwide sites were included (median age 37 years; 52% male). There were a total of 1230 ABCD infusions (mean dose 2.8 mg/kg/day); 90% of the infusions (1105/1230) had pre-medication. Common pre-medications included corticosteroids, antihistamines, paracetamol (acetaminophen) and metamizole. The overall IRR rate was 12% (147/1230) and was lower in infusions with pre-medication (11%) versus no pre-medication (22%), P < 0.001. Corticosteroids were associated with a decreased incidence of IRRs (P < 0.05), while paracetamol and antihistamines were not. The most common IRRs were chills (7%), fever (7%) and rigors (5%). Clearance of the fungal infection occurred in 52% of the participants. CONCLUSIONS: These data suggest a lower rate of IRRs with ABCD than previously reported. Pre-medication is associated with decreased IRR incidence. Corticosteroids in particular appear to decrease IRRs while paracetamol and antihistamines, though commonly used, do not.

[The treatment of febrile immunosuppressed patient]. / Lijecenje febrilnog imunosuprimiranog bolesnika.

Infections are a major cause of morbidity and mortality in immunocompromised patients. The recognition and treatment of infections in this patient population are particularly difficult task for several reasons: the clinical manifestation of infection may be indistinguishable from those of the underlying disease; the effect of immunosuppressive therapy may diminish the usual disease manifestation; the spectrum of potential pathogens is large, making empirical treatment difficult. Fever with or without a clinically obvious source is a frequent presenting feature of serious infections in immunosuppressive patients. Pneumonia is one of the most frequent life-threatening infections in patients receiving immunosuppressive therapy.

[Classical type of Fabry disease without angiokeratomas--a case report]. / Klasicni oblik Fabryjeve bolesti bez angiokeratoma--prikaz bolesnika.

A patient with classical type of Fabry disease is described. The appearance and character of neuropathic pain during hemodyalisis is described. Characteristic changes in head shape and changes of hands and fingers are the additional phenotypic characteristics of Fabry disease. Enzyme replacement therapy administered in the early phase of the disease could prevent disease complications and early patient's death.

[Diagnosis and treatment of Gaucher disease in Croatia]. / Dijagnoza i lijecenje Morbus Gaucher u hrvatskoj.

Gaucher disease is the most common lysosomal storage disorder. Incidence of disease is around 1:40-60,000 inhabitants and it is assuming that in Croatia we have 20-30 patients with Morbus Gaucher. Morbus Gaucher is recognized in three types. Type I or so called non-neuropatic from is most common in Europe while so called neuropatic forms (type II and III) are much rare (5-10%). Type II and III are characterized by central nervous system involvement and usually are diagnosed in childhood. Disease manifestations are observed in various human organs. The most common disease features are involved liver, spleen, bones, lungs and brain. Enzyme replacement therapy with imiglucerase (Cerezyme) is now day's therapeutic gold standard. Imiglucerase prevents progressive manifestation of disease and patients have normal life. Cost of the treatment is high due to the cost of the recombinant technology which was used to product imiglucerase. The cost of the enzyme replacement therapy is 150-200,000 EUR per year for imiglucerase in a typical adult patient. Because of high cost for the patient treatment Ministry of Health of Republic of Croatia, and Croatian Health Insurance Company in year 2002. established a special program for so called "Expensive drug treatment". This program covering treatment costs for patients with inherited metabolic disorders, adenosine deaminase deficiency, chronic myeloid leukemia, AIDS, multiple sclerosis, juvenile arthritis and ovarian cancer. Until now 11 adult patients and 2 children with Gaucher disease were diagnosed in Croatia and all are on enzyme replacement therapy with imiglucerase. According to our experience administration of imiglucerase decreased spleen and liver size and number of bone pain crisis as well as normalization of platelet and red blood cells. Administration of the imiglucerase do no revert bone changes e.g. avascular hip necrosis or vertebra collapses, but prevent further bone deterioration. According to this, treatment with imiglucerase should be started immediately after establishing diagnosis to prevent irreversible changes on human organs.

[Ocular findings in Fabry's disease]. / Fabryjeva bolest i promjene na ocima.

INTRODUCTION: Fabry's disease is a recessive X-linked disorder that results from a deficiency of the lysosomal hydrolase a-galactosidase A (alpha-Gal A). The absence of alpha-Gal A enzyme activity leads to accumulation of glycosphingolipid globotryaosyl ceramide (GL-3) in the lysosomes of a variety of cell types. Subsequently, angiokeratoma and ocular signs develop until, in most cases after the third decade of life, severe renal dysfunction or cardiomyopathy becomes obvious. Corneal opacities (cornea verticillata) occur in 90% conjunctival vascular changes in 60%, retinal vessel tortuosity in 55%, and cataracts in 50% of cases. Recently, enzyme replacement therapy has been shown to be an effective treatment modality that can eliminate glycolipid stores and reverse the disease pathology. CASE REPORT: A male patient born in 1971 was admitted for clinical examination due to proteinuria and erythrocyturia. During further evaluation nephrologist suspected Fabry's disease, because patient had skin changes early referred as petechiae, and acroparesthesias. He had also low heat tolerance and virtually no sweat. Physical status: angiokeratoma on gluteat regions and upper arms. Urine analysis in several occasions 10-15 E in sediment, alb. positive. On ECG, 2-mm depression of ST in precordial region. Heart ultrasound: low mitral regurgitation angio stage 1, left ventricle hypertrophy. Abdomen ultrasound: both kidneys around 12 cm large, parapyelic cysts in both kidneys of 2.5 cm in diameter. Biomicroscopy of both eyes: cornea verticillata. Fundus of both eyes: papillae n. optici with poorly defined edges, but without prominence, very tortuotic retinal blood vessels. In March 2002, very low alpha GAL enzyme activity in blood (alpha-Gal A = 0.5 +/- 0.2 nmol of substrate hydrolyzed hourly per serum mL--normal serum enzyme level 8.5-18.9 nmol/mL/h). In May 2002, enzyme replacement therapy was started with recombinant alpha-Gal A enzyme (Fabrazyme) 1 mg/kg every 14 days. Control evaluation and examination showed good cardiac and renal function. The patient felt better and stronger with improved heat tolerance. CONCLUSION: Fabry's disease occurs in all ethnic groups. It is estimated that one in 200 people is a carrier, and one in 40,000-100,000 has the disease. Today in Croatia, Fabry's disease has been diagnosed in only one patient, and according to the usual prevalence there are still 45-100 unrecognized patients. The ophthalmologists are in excellent position to diagnose Fabry's disease in early stages. Therefore it is very important that the ophthalmologists in Croatia become aware of the importance of ocular findings in Fabry's disease, so they can participate in the identification of unrecognized patients.

Gemcitabine in the treatment of relapsed and refractory Hodgkin's disease.

BACKGROUND: Patients with refractory Hodgkin's disease or relapsing after high-dose therapy and autografting have a poor prognosis. Here, we present our experiences with gemcitabine in this setting. PATIENTS AND METHODS: We treated 14 patients with relapsed or refractory Hodgkin's disease with gemcitabine. The treatment was given on a compassionate use basis, off-label and not according to a study protocol. Patients were 17-46 years of age. 1 patient had stage IA disease, 2 patients had stage IIIB disease and 11 patients had stage IVB disease. 9 patients had received radiotherapy. 8 patients had been autografted and 1 patient auto- and allografted. Gemcitabine was administered at a starting dose of 1 g/m(2) on days 1 and 8 every 3 weeks in combination with steroids. RESULTS: The median follow-up period was 10 months. Hematological toxicity grade 3-4 occurred in 12 patients leading to dose reductions. 1 patient died of neutropenic sepsis. No other non-hematological toxicities were observed. The response rate was 64% with 6 patients achieving complete remission (CR) and 3 patients partial remission (PR). The median time to treatment failure was 9 months, and survival was 11 months. Responses were seen in previously transplanted patients and in patients refractory to previous treatment. The so far longest responder has been in CR for over 68 months. CONCLUSION: Gemcitabine is an effective treatment for Hodgkin's disease. Heavily pretreated patients often require dose reductions.

[Risk factors for invasive fungal infections during intensive chemotherapy of acute leukemia--retrospective study]. / Cimbenici rizika invazivnih gljivicnih infekcija tijekom intenzivne terapije akutnih leukemija--retrospektivna studija.

AIM: The incidence, outcome and risk factors for developing invasive fungal infection were retrospectively analyzed in 150 patients with acute leukemia during intensive cytostatic therapy. PATIENTS AND METHODS: Patients with and without the diagnosis of fungal infection were compared according to age, sex, diagnosis, stage of disease, type of therapy, antimicrobial prophylaxis, duration of febrile episodes, duration of antimicrobial therapy, duration of antifungal therapy, chest x-ray findings, results of surveillance cultures for fungal species isolation, clinical diagnosis at discharge from hospital, and autopsy findings. Clinical findings in patients with confirmed fungal infection on autopsy were analyzed separately. RESULTS: The incidence of fungal infection according to clinical diagnosis was 38.5%. The incidence among patients who died during therapy at autopsy was 78.5%. The incidence of Candida and Aspergillus infections at autopsy was 40% and 60%, respectively. Specific incidence could not be determined during life. The mortality was 59% in the group of patients with fungal infection, and 43% in the group of patients without fungal infection. During the study, an increase in the rate of fungal infection as well as a trend to prolonged survival of these patients were observed. On multivariate analysis, independent risk factors associated with a greater incidence of fungal infection were duration of hospitalization (p=0.04), duration of granulocytopenia with granulocyte count less than 0.5x10(9)/L (p=0.05), number of febrile episodes (p=0.01), duration of febrile episode (p=0.001), intestinal decontamination (p=0.02), duration of antibiotic therapy (p=0.01), positive chest x-ray finding (p=0.001), and year of therapy (p=0.02). On univariate analysis, a greater incidence of fungal infections was also associated with younger age, acute lymphatic leukemia, newly diagnosed disease and second relapse of the disease. The occurrence of fungal infections showed no correlation with the type of therapy, number of chemotherapy cycles, type of fungal species isolated from particular locations and frequency of colonization at particular locations. However, the number of colonized locations and number of fungal species was two to three times greater in patients with than in those without fungal infection. CONCLUSIONS: Fungal infections are becoming an increasing problem during intensive therapy of acute leukemia and contribute to poor therapy outcome. The diagnosis of fungal infection during life is extremely difficult and frequently late. There is the need of a more precise diagnostic test that would provide earlier diagnosis. The knowledge of risk factors is helpful in the diagnosis and therapy of fungal infections. The suspicion of fungal infection in patients at risk justifies the introduction of antifungal therapy and contributes to better therapeutic outcome.

[Gaucher disease: diagnosis and treatment]. / Gaucherova bolest: dijagnostika i mogucnosti lijecenja.

Gaucher's disease is the most common lysosomal storage disorder. It was identified in 1882 by Phillipe Gaucher, a French dermatologist. However, it was not until 1965 that Gaucher disease was found to be due to a deficiency in the enzyme glucocerebrosidase (EC 3.2.1.45) which breaks down glucocerebroside, a cell membrane component. The deficiency in this enzyme leads to an accumulation of glucocerebroside within the lysosomes of macrophages throughout the body. Gaucher's disease is classified into three types: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). Of the three, type 1 is the most common, affecting one in 40,000-200,000 people and having a high prevalence among Ashkenazi Jews, affecting one in 450-1500. The signs and symptoms of type 1 disease demonstrate marked heterogeneity, from asymptomatic or mildly symptomatic, to severe disability with disfigurement and even death. Hepatosplenomegaly and thrombocytopenia are well documented. Less well-recognized are often insidious skeletal complications which affect the majority of type 1 patients and which are its most debilitating feature. In addition to clinical suspicion, some morphologic, hematologic and biochemical indicators can help establish the diagnosis. However, definitive diagnosis is only made by determining the catalytic activity of the lysosomal enzyme glucocerebrosidase. Confirmation of heterozygosity requires the use of molecular biotechnology methods. About 150 mutations of the glucocerebrosidase gene have been identified in patients with Gaucher's disease, some of which are predictive of phenotype. The history of treatment of Gaucher disease started with splenectomy and continued with bone marrow transplantation, before the recent introduction of safe and effective enzyme replacement therapy. In Croatia, nine patients with type 1 Gaucher's disease have been identified so far. Seven patients are on enzyme replacement therapy, and past results demonstrated significant improvement in all clinical symptoms, without development of any side effects. However, new treatments, such as substrate balance therapy and gene therapy, may become available within the next few years. The place, if any, that such therapies will have in the treatment of patients with Gaucher's disease will be dependent on the results of clinical studies currently in progress.

Management of Gaucher disease in a post-communist transitional health care system: Croatian experience.

AIM: To evaluate the feasibility of financing the treatment of Gaucher disease with recombinant human imiglucerase in the Croatian health care system. METHODS: Treatment with enzyme replacement therapy of 5 patients with Gaucher disease was started on January 2001. In 4 patients the typical signs of Gaucher disease (organomegaly, bone changes, anemia, and thrombocytopenia) were documented at the time of diagnosis. One patient received bone marrow stem cell transplant as treatment for acute myeloid leukemia from a HLA-matching sibling with Gaucher disease. All patients underwent therapy with imiglucerase (Cerezyme) infusion every 14 days. The outcome and actual cost of the treatment were followed during 12 months. RESULTS: After 3 months of therapy, hemoglobin rose above low normal range in 2 patients. After 6 months, 3 patients had platelet count above 100x10(9)/L, and bone pain crises completely disappeared in patients with severe bone involvement. After 12 months, normal blood counts were restored in all patients. At the same time point, bone destruction remained unchanged in 3 patients and showed marked improvement in one. In agreement with the Ministry of Health, the Croatian Institute for Health Insurance restructured its funds and established a special "Fund for expensive drugs." This fund covers the treatment costs for patients with Gaucher disease (approximately 150,000 per patient per year) as well as the cost of treatment for patients with Fabry disease, AIDS, adenosine deaminase deficiency, multiple sclerosis, chronic myeloid leukemia, juvenile arthritis, and ovarian cancer. CONCLUSION: Collaboration of the institutions in a post-communist transition health care system can provide an effective model for financing expensive treatment for patients with rare diseases in a resource-poor health system.

Combination of ifosfamide, methotrexate, and etoposide (IMVP) as a salvage therapy for relapsed and refractory aggressive non-Hodgkin lymphoma: retrospective study.

AIM: There are contradictory reports on the outcomes of IMVP (ifosfamide, methotrexate, and etoposide) treatment in patients with aggressive non-Hodgkin s lymphomas. Our aim was to evaluate retrospectively the results of this treatment in our institution. METHODS: Twenty eight patients with refractory or relapsed aggressive non-Hodgkin s lymphomas received IMVP between April 1997 and June 2001. Median follow-up of the survivors was 24 months. There were 15 women and 13 men, aged 15-68 years. Twelve patients were refractory to primary treatment. The number of previous treatment lines varied between one and five. The overall response rate to IMVP treatment was 39%, with 6 patients achieving complete and 5 partial response/remission. Eleven patients received a subsequent hematopoietic stem cell transplant after IMVP therapy. RESULTS: Median duration of the survival for all patients was 6 months, and the response duration for responders 6 months. Nine patients had grade 3 hematologic toxicity or higher, 5 developed significant infectious complications, and one developed the tumor lysis syndrome. There was one treatment-related death due to infection. The patients with a low or low-intermediate international prognostic index at the start of IMVP had a significantly better survival and progression-free survival rates than those with high or high-intermediate score. Seven patients with hematopoietic stem cell transplant were alive in December 2001. CONCLUSION: IMVP is an active regimen with acceptable level of toxicity in patients with relapsed or refractory aggressive non-Hodgkin s lymphoma. However, outcomes of this treatment are unsatisfactory and better treatment is still needed.